1998 Fiscal Year Final Research Report Summary
Molecular analysis of X-linked agammaglobulinemia (XLA) and Bruton's tyrosine kinase (Btk)
| Project/Area Number |
09670154
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
TSUKADA Satoshi Osaka University Medical School, Assistant Professor, 医学部, 助手 (60273637)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Shoji Osaka University Hospital, Medical staff, 医学部・付属病院, 医員
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| Project Period (FY) |
1997 – 1998
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| Keywords | agammaglobulinemia / Bruton's tyrosine kinase / Sab / immunodeficiency |
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| Research Abstract |
X-linked agammaglobulinemia (XLA), one of the most popular hereditary immunodeficiencies, exhibits the typical B-limphocyte deficiency characterized by a complete absence of humoral immunity.The dificient gene product in XLA is known as Btuon's tyrosine kinase (Btk).We have been investigating the pathogenisis of XLA from both clinical and molecular aspects.
1. We analized the function of the Btk-binding protein Sab (SH3-domain binding protein which preferentially associates with Btk), which we previously reported as a newly-identified SH3 domain-binding protein.Sab was shown to inhibit the auto- and transphosphorylahion activity of Btk, which prompted us to propose that Sab functions as a transregulator of Btk.Forced overexpression of Sab in B cells led to the reduction of BCR-induced tyrosine phosphorylation of Btk and significantly reduced the B cell antigen receptor-mediated early and late events including calcium mobilization, inositol 1, 4, 5-triphosphate production as well as apoptotic cell death in which the involvment of Btk activity has been previously shown.These results indicate the negative regulatory role of Sab in the B cell cytoplasmic tyrosine kinase pathway.
2. To understand the Btk signaling pathway, we have further searched the molecules which interact with Btk.We identified that one of the major Btk-SH2 domain binding proteins in B cells is BLNK (B cell linker protein) and present evidences that the interaction of BLNK and the SH2 domain of Btk contributes to the complete-tyrosine phosphorylation of phospholipase Cgamma, which leads the B cell antigen receptor-coupled clacium signaling to open.
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[Publications] Futatani, T., Tsukada, S., Hashimoto, S., Matsushita, M., Yamadori, T., Niida, Y., Kunikata, T., Arai, . S., Kurimoto, M., Imamura, H., Kishimoto, T., and Miyawaki, T.: "Flowcytometric detection of Bruton's tyrosine kinase deficiency and its carrier in X linked agammaglobulinemia." Blood. 91. 595-602 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Matsushita, M., Yamadori, T., Kato, S., Takemoto, Y., Inazawa, J., Baba, Y., Hashimoto, S., Sekine, S., Arai, S., Kunikata, T., Kurimoto, M., Kishimoto, T.and Tsukada, S.: "Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (Btk)." Biochem.Biophys.Res.Commun.245. 337-343 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Nonoyama, S., Tsukada, S., Yamadori, T., Miyawaki, T., Jin, Y.Z., Watanabe, C., Morio, T., Yata, J-1.and Ochs, H.D.: "Functional analysis of the peripheral B cells in patients with X-linked agammaglobulinemia." J.Immunol.161. 3925-3929 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Hashimoto, S., Miyawaki, T., Futatani, T., Kanegane, H., Usui, K., Nukiwa, T., Namiuchi, S., Matsushita, M., Yamadori, T., Suemura, M., Kishimoto, T.and Tsukada, S.: "A typical X-linked agammaglobulinemia (XLA) patients diagnosed in their adult ages." Internal Medicine. (in press).
Description
「研究成果報告書概要(欧文)」より
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[Publications] Baba, Y., Nonoyama, S., Matsushita, M., Yamadori, T., Hashimoto, S., Imai, K., Arai, S., Kunikata, T., Kurimoto, M., Kurosaki, T., Ochs, H.D., Yata, J-I., Kishimoto, T.and Tsukada, S.: "WASP is involved in the tyrosine kinase pathway in B-lineage cells." Blood.93. 2003-2012 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Maeda, A., Scharenberg, A.W., Tsukada, S., Bolen, J.B., Kinet, J-P.and Kurosaki, T.: "Paired Immunoglobulin-like receptor B (PIR-B)inhibits BCR-induced activation of Syk and Btk by SHP-1." Oncogene.(in press).
Description
「研究成果報告書概要(欧文)」より
